Smooth muscle contractile activity is an important regulator of vascular tone and blood pressure. We are probing the relationship between ion metabolism at the single cell level and blood pressure regulation in vivo using interventions which alter mean systolic blood pressure. 30 mo. old Fisher 344XNB rats showed a significant elevation in systolic blood pressur (155.3+1.64 mm) compared to their 6 mo. old counterparts (131.3+5.96 mm; p<.001). Other studies by us have shown that smooth muscle relaxation induced by ~-agonists involves a depletion of SR Ca2+ stores which are essential for contraction. Addition of the ~-adrenergic receptor (BETA) agonist isoproterenol (ISO) to freshly-isolated rat arterial smooth muscle cells (SMC) reduced SR Ca2+ content to a greater extent in young cells (30.74+7.76% of the pre-ISO level) than in old cells (37.6+2.36%; p<.05). Fish oil diets containing polyunsaturated fatty acids have a blood pressure lowering effect. Dietary supplementation with saturated fatty acids, which increased mean systolic blood pressure in 8 and 12 mo. old rats (p<.05), increased SR Ca2+ levels following exposure to ISO. In contrast, supplementation with fish oil, which reduced blood pressure significantly i 12 and 24 mo. old rats (p<.01), decreased SR Ca2+ following beta-stimulation. Rats given 25% D2O in their drinking water showed an average decline in systolic blood pressure of 35 mm compared to control animals without D2O. Single SMC prepared from D2O-treated rats displayed a lower SR Ca2+ content compared to control cells after exposure to ISO in H2 buffer. Thus, interventions that raise blood pressure also raise SR Ca2+ while agents lowering blood pressure reduce SR Ca2+. This qualitative correlation is compatible with the view that higher residual SR Ca2+ levels following ~-stimulation lead to enhanced smooth muscle contractile activity in the presence of vasoconstrictors, thereby contributing to an elevation i blood pressure.